Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to a sustained-release formulation, and more specifically, to a sustained-release formulation which is suitable for poorly soluble antibiotics, for veterinary use.
• Sustained release of a drug following parenteral administration is generally preferable to oral administration in veterinary medicine and allows the treatment of large domestic animals (such as cattle) as well as pets and other animals. Reducing the dosing frequency is known to improve patient safety, reduce the incidence of injection site complications and improve compliance with drug protocols. Sustained release formulations mitigate the bolus effect at the time of injection, and thus have a salutary influence on drug side effects. For certain prophylactic uses and treatments, one-time administration or infrequent administration has become a standard procedure. For example, monthly administration is available in most heartworm preventatives such as Heartguard®, Sentinel® and Interceptor medications.
• Controlled release parenteral formulations may be in the form of liquids, in situ forming solids and solids [Medlicott et al., Advanced Drug Delivery Reviews 2004, 56:1345-1365] Best-selling parenteral controlled release products include Posilac® milk enhancer (a liquid suspension), Micotil® antibiotic (a liquid solution), Nuflor® antibiotic (a liquid solution) and Revalor® growth enhancer (a solid implant).
• Poloxamers are nonionic triblock copolymers which consist of blocks of relatively hydrophilic poly(ethylene oxide) (PEO) and relatively hydrophobic polypropylene oxide) (PPO) arranged in A-B-A tri-block structure: PEO- PPO-PEO.
• PEO poly(ethylene oxide)
• PPO polypropylene oxide
• Poloxamer aqueous gels are described, for example, in U.S. Patent No. 3,740,421. Poloxamers are used as emulsifying agents for intravenous fat emulsions, as solubilising agents to maintain clarity in elixirs and syrups, and as wetting agents for antibacterials.
• the hydrophobic-lipophilic balance (HLB) of a poloxamer may be characterized by the numbers of ethylene oxide and propylene oxide units in the copolymer. Due to their amphiphilic nature, poloxamer copolymers display surfactant properties, including an ability to interact with hydrophobic surfaces and biological membranes. In aqueous solutions at concentrations above the critical micelle concentration (CMC) these copolymers self-assemble into micelles. The diameters of poloxamer micelles usually vary from approximately 10 nm to 100 nm.
• the core of the micelles consists of hydrophobic PPO blocks that are separated from the aqueous exterior by a hydrated shell of PEO blocks.
• the core is capable of incorporating various therapeutic or diagnostic reagents [Bartrakova & Kabanov, Journal of Controlled Release 2008, 130:98-106] Poloxamers are generically designated with the letter P (for“poloxamer”) followed by three digits. The first two digits multiplied by 100 give the approximate molecular mass of the PPO core, and the last digit multiplied by 10 gives the percentage of PEO.
• P407 is a poloxamer with a PPO molecular mass of 4,000 Da, and a 70 % PEO content.
• the copolymer is designated with a letter which defines its physical form at room temperature, L for liquid, P for paste, F for flake (solid), followed by two or three digits.
• L61 is a liquid poloxamer with a PPO molecular mass of 1,800 Da, and a 10 % PEO content, which would be designated as P181 according to the designation system described above.
• Ei.S. Patent Application No. 20090214685 describes a thermoplastic pharmaceutical composition comprising botulinum toxin and a biocompatible poloxamer.
• the pharmaceutical composition can be administered as a liquid, and gels after administration into a sustained release drug delivery system from which the botulinum toxin is released over a multi-day period.
• U.S. Patent No. 7,008,628 describes a pharmaceutical composition which comprises a linear block copolymer such as a poloxamer, end-modified by a bioadhesive polymer such as polyacrylic acid. The polymer is capable of aggregating in response to an increase in temperature.
• Florfenicol is a commonly used broad-spectrum antibiotic agent, used for the treatment of Swine Respiratory Diseases (SRD) among other uses.
• the approved veterinary products of florfenicol include injectable formulations usually containing 300 mg/ml.
• One of such approved product for said injectable formulation for veterinary use is dissolved in an organic solvent N-methyl pyrrolidone (NMP).
• NMP N-methyl pyrrolidone
• Some formulations for sustained release of florfenicol were previously disclosed, including Chinese Patent Application CN103202802, directed to sustained release formulations which include poloxamers and polysaccharides.
• the disclosure relates to several different polysaccharides and varied loadings of the active agent florfenicol in said formulations.
• the present invention provides a composition comprising a poorly soluble antimicrobial agent, at least one poloxamer, an organic solvent, and a cellulose derivative which is at least partially soluble in organic solvents, and an aqueous medium, wherein said composition is injectable. It was further surprisingly found that at very high loading of the active material e.g. above 35 wt% or 40 wt%, the combination of poloxamer and organic solvent in water may be sufficient to provide an injectable formulation having a consistent and reproducible release profile.
• the present invention provides a composition comprising an antimicrobial agent, at least one poloxamer, an organic solvent, and an aqueous medium, wherein the concentration of said antimicrobial is above 35 wt% to above 40 wt%, and wherein said composition is injectable.
• a pharmaceutical composition comprising a biologically active agent, poloxamer, an aqueous carrier, and an organic co-solvent, wherein said composition is an injectable composition at room temperature, with a proviso that wherein said active agent concentration is below 35 wt% the composition further comprises a cellulose-based material which is at least partially soluble in organic solvents.
• the concentration of the drug when the concentration of the drug is above 35 wt%, e.g. from 35 wt% and up to 50 or 55 wt%, the cellulose-based material is included.
• the concentration of the drug is above 35 wt%, e.g.
• composition is devoid of cellulose-based material, e.g. between 40 wt% and 50 wt%, or between 42.5 wt% and 50 wt%, or between 45 wt% and 50 wt%.
• a pharmaceutical composition comprising a biologically active agent, poloxamer, an aqueous carrier, an organic co-solvent, and a cellulose-based material which is at least partially soluble in organic solvents, wherein said composition is an injectable composition at room temperature, and wherein a concentration of said biologically active agent is above 10 wt%, and up to 35 wt%.
• the biologically active agent may be selected from florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tylvalosin, doxycycline, and oxytetracycline.
• the biologically active agent is florfenicol.
• florfenicol may be present in the composition in a loading of between about 25 wt% to about 50 wt%.
• the organic co- solvent may be present at an amount of between about 5 to about 15 %wt.
• the cellulose- based material which is at least partially soluble in organic solvents may be hydroxypropyl cellulose.
• the organic solvent may be selected from the group consisting of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), PEG 400, propylene glycol, and ethanol.
• NMP N-methyl pyrrolidone
• DMSO dimethyl sulfoxide
• PEG 400 propylene glycol
• ethanol propylene glycol
• the organic solvent is N-methyl pyrrolidone.
• the pharmaceutical composition comprises the organic solvent which is N-methyl pyrrolidone, and the cellulose-based material which is at least partially soluble in organic solvents is hydroxypropyl cellulose, and biologically active agent is florfenicol at a concentration of at between 25 wt% and 50 wt %.
• the pharmaceutical composition comprises the organic solvent which is N-methyl pyrrolidone, and florfenicol in a concentration between 35 wt% and 50 wt%.
• the composition is administered once to said non-human animal per the course of treatment.
• the administration comprises intramuscular injection, or subcutaneous injection.
• the infection may be caused by a swine pathogen.
• Figure 1 schematically represents the release profiles of florfenicol from selected compositions.
• Figure 2 schematically represents the release profiles of florfenicol as the effect of added organic solvent.
• Figure 3 represents the blood plasma concentrations of florfenicol following single administration of a composition according to the invention, versus two administrations of a commercial product.
• Figure 4 represents the blood plasma concentrations of florfenicol following single administration of further compositions according to the invention, versus two administrations of a commercial product.
• the sustained release composition of the present invention comprises an active biological agent.
• said biological agent is preferably an antimicrobial agent, which demonstrates a poor solubility in aqueous media.
• the poor solubility may be understood as defined, e.g. in the current United States Pharmacopeia, but may be better understood in the context of the formulation, as explained in more detail below.
• the antimicrobial agent utilized in the sustained release composition of the invention is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tylvalosin, doxycycline, and oxytetracycline.
• the antimicrobial agent is florfenicol.
• the loading i.e. the amount of biologically active agent or antimicrobial agent which is introduced in the injectable dosage form
• the high loading of the injectable composition of the invention is promoted, among other factors, by having a formulation comprising a biologically active agent which may be in an insoluble form, thereby forming a dispersion in the aqueous medium.
• the antibacterial agent dispersed in the formulation is, to some extent, in a solid form.
• more than 90% of the drug is in insoluble form, but the drug may be as much as 99.999% in an insoluble form.
• the insoluble form of the drug usually includes base compounds, or salts particularly having low water solubility, even if a more soluble salt may be known.
• the loading may vary.
• the drug readily interacts with the aqueous medium or with poloxamer or other surface-active agents, it may form a paste, i.e. a composition that is not readily uptaken with a syringe (non-syringeable) and/or not injectable, at high loading values.
• such drugs may be used at rather low loading values, e.g. between 12 and 20 %wt, but generally preferably the drug loading is high.
• the loading is at least about 20 wt % of the injectable composition.
• the loading is between about 25 to about 30 wt % of the injectable composition. In some other embodiments, the loading is at least about 30 wt % of the injectable composition. In some further embodiments, the loading is between about 30 to about 45 wt % of the injectable composition. In some further embodiments, the loading is between about 35 to about 50 wt % of the injectable composition. In some embodiments, the loading is between about 30 to about 35wt % of the injectable composition.
• florfenicol loading used for a specific applications may be between 25 and 50 wt%, such as between 28 and 32 wt%, or between 36 and 42 wt%, or between 44 and 48 wt%.
• the biologically active agent forms dispersion in the aqueous medium with the co-solvent. It is understood that the biologically active agent should be in a form of solid, e.g. powder. The powder may be in form of aggregates, granulation, or coated powder, but preferably the powder is neat drug substance powder, of a defined particle size distribution.
• the powder has the particle size of less than about 90 microns, more preferably less than about 50 microns. It may sometimes be advantageous also to use smaller particle sizes, or even micronized powder. Without being bound by a theory it is believed that powder of smaller particle size may increase the peak plasma concentration obtainable from a formulation in vivo, in comparison to regular drug powder, even if in vitro the difference would be small or insignificant. Micronized powder or powder with reduced particle size may be obtained directly from the powder of the biologically active substance, as generally known in the art, e.g. by high-impact or high-shear milling, sieving under pressure, and in other ways.
• the biologically active material or antimicrobial agent is released from the in-situ formed gel of the composition of the present invention during at least 3 days. In some other embodiments, the material is being released over between 2 to 3 days. In some further embodiments, the material is being released over between 4 to 5 days. In some embodiments, the material is being released over more than 5 consecutive days from a single injectable composition of the invention.
• the release may be thus described in terms of release duration rather than any specific rate.
• the duration of the release in vivo may be detected in the plasma as the drug concentrations maintaining significant levels over time. In another embodiment, the duration of the release in vivo may be detected in the target organ or tissue as the drug concentrations maintaining significant levels over time.
• the duration of the release may be detected in blood plasma, and the concentrations obtained may be compared to the minimum inhibitory concentrations of the antibiotics for specific pathogens.
• the duration of the drug release may be from about 12 hours to about 3 days, e.g. in the conditions as described in the Examples section below.
• the drug loading in the formulations comprising such cellulose derivative may be as low as about 5 wt%, or about 10 wt%. However, depending on the antibiotic solid-state properties, the drug loading may be as high as 35 wt%, or 40 wt%, or 45 wt%, or 47.5 wt%, or even 50 wt%. Moreover, when the active agent is present in a concentration of above 35 wt%, it has been unexpectedly found that relatively stable and repeatable drug release kinetics may be achieved from compositions comprising poloxamer, water and an organic co-solvent as defined herein.
• the release profiles without the excipient were surprisingly consistent enough to meet the requirements of the current United States Pharmacopiea for the variability of the drug release of the controlled-release dosage forms.
• the composition comprise the cellulose derivative as describes below.
• the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237 and poloxamer 338, and combination thereof. In some currently preferred embodiments, the poloxamer as described above is poloxamer 407.
• poloxamer allows the composition to gel under physiological temperature, and hence, said poloxamer must exist in a suitable concentration in the injectable composition to enable the formation of a stable gel, particularly in presence of a large amount of the undissolved powder of the active agent. Accordingly, the concentration of the poloxamer as described above is above 8 weight percent from the total weight of the formulation.
• the amount of poloxamer may be as low as 7 to 9 wt% and up to 16 to 20 wt%.
• the synergistic effect of some of the embodiments of the present invention is achieved by combining said poloxamer with a unique combination of an organic co- solvent and a cellulose derivative which is at least partially soluble in organic solvents.
• the chemical compatibility between the cellulose derivative and the organic solvent, and the ratio between these two components determine, together with the poloxamer concentration, the release profile of the biologically active agent.
• the organic solvent may be increasing the solubility of the biologically active agent, it also slows down the release rate of said active agent from the gel-form composition under physiological conditions, due to its effect on the gel itself.
• the addition of the cellulose derivative as described above may be responsible for the increase in the biologically active agent release rate, and that the organic solvent contributes to a reduced variability in the overall release profile over time.
• the molecular weight of the cellulose derivative to be used may be selected according to the rheological properties required and the contemplated release profile, according to the some embodiments of the present invention, the concentration ratio between said cellulose derivative and said organic solvent may usually be between about 1 :6 to about 1 :20.
• the concentration ratio between said cellulose derivative and said organic solvent may be between about 1 : 10 to about 1 : 100.
• the cellulose derivative which is at least partially soluble in organic solvents is usually such that it dissolves to some appreciable extent in common pharmaceutical organic solvents, e.g. in ethanol.
• the suitable derivative forms a clear solution upon dissolution of, e.g. 1 gram of the derivative in 100 mL of 96%-ethanol at room temperature.
• One suitable cellulose derivative which is at least partially soluble in organic solvents is hydroxypropyl cellulose. Hydroxypropyl cellulose possesses a further useful property that it is also highly soluble in aqueous solutions at room temperatures and becomes less soluble with increased temperature.
• the concentration of the cellulose derivative as described above is between about to about 0.5 wt% to about 1.5 wt% of the total weight of the injectable composition. In some other embodiments, the cellulose derivative concentration is between about 0.5 to about 1 wt%. When the drug is present in a very high loading, e.g. above 40%, the cellulose derivative concentration may be between about 0.05 to about 0.7 wt%.
• the organic solvent as described above is selected from the group consisting of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), PEG 400, propylene glycol, and ethanol.
• NMP N-methyl pyrrolidone
• DMSO dimethyl sulfoxide
• PEG 400 PEG 400
• propylene glycol PEG 400
• propylene glycol propylene glycol
• ethanol propylene glycol
• the organic solvent is NMP.
• the concentration of the organic solvent as described above is between about to about 1.5 wt% to about 20 wt% of the total weight of the injectable composition. In some other embodiments, the organic solvent concentration is between about 3 to about 15 wt%. In yet some other embodiments, the organic solvent concentration is between about 8 to about 12 wt%.
• At least one poloxamer, an organic solvent, and the cellulose derivative are dissolved in an aqueous medium.
• the aqueous medium is usually water, optionally comprising further dissolved additives, such as salts and/or buffers.
• the amount of the aqueous medium in the preparation is usually the remainder from the 100% of the composition upon subtraction the respective percentages of the biologically active agent, the at least one poloxamer, the cellulose derivative, the co- solvent, and other excipients if used.
• the salts may include sodium chloride, calcium chloride, or magnesium chloride
• the buffers may include mono-, di-, or tri-basic salts of alkali metals and phosphates.
• the cellulose derivative which is at least partially soluble in organic solvents, and poloxamer in an aqueous medium is clearly beneficial, when the drug is present in very high loading, e.g. above 35 wt% to above 40 wt%, the effect of cellulose derivative on the stabilization of the system may become less required to obtain a pharmaceutically acceptable composition, e.g. demonstrating the release profile with the relative standard deviation in the concentrations’ values at each time point of below 10%. As demonstrated in the examples below, e.g.
• the formulation achieved is a stable and injectable formulation at room temperature (e.g. between 15 °C and 25 °C), or on cold (e.g. between 2 °C and 8 °C), which upon injection into the animal body (e.g. having a temperature above 35 °C) transforms into a gel form, characterized in having a reproducible and well-controlled release profile of the biologically active agent incorporated therein.
• room temperature e.g. between 15 °C and 25 °C
• cold e.g. between 2 °C and 8 °C
• the present invention provides a preparation method of injectable sustained release formulations comprising antimicrobial agent, at least one poloxamer, an organic solvent, and a cellulose derivative which is at least partially soluble in organic solvents, in an aqueous medium, having the steps of : 1) mixing water and organic solvent (known as co-solvent) and preferably cooling the resultant mixture, 2) adding consecutively or concomitantly the at least one poloxamer and said cellulose derivative into the [cold] mixture of step 1, followed by mixing until dissolution; and 3) adding the antimicrobial agent into the resultant mixture.
• a preparation method of injectable sustained release formulations comprising antimicrobial agent, at least one poloxamer, an organic solvent, and a cellulose derivative which is at least partially soluble in organic solvents, in an aqueous medium, having the steps of : 1) mixing water and organic solvent (known as co-solvent) and preferably cooling the resultant mixture, 2) adding consecutively or concomitantly the at least one poloxamer and said cellulose derivative
• the organic solvent as described above is selected from the group consisting of N-methyl pyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol. In some currently preferred embodiments, the organic solvent is NMP.
• the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237, poloxamer 338, and combination thereof. In some currently preferred embodiments, the poloxamer as described above is poloxamer 407.
• the cellulose derivative is hydroxypropyl cellulose.
• the antimicrobial agent utilized in step 3 is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulamethoxazole, pleuromutilin, avilosin, tylvalosin, doxycycline, oxytetracycline.
• the antimicrobial agent is florfenicol.
• co-solvent refers to the organic solvent which is mixed with the aqueous carrier or water in the formulation of the invention.
• the organic solvent as described above is selected from the group consisting of N-methyl pyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol.
• a method of treatment of veterinary infections, or use of the compositions in treating of the veterinary infections by administering to a patient in need thereof at least one injection of an injectable sustained release compositions as generally described herein, comprising, in an aqueous medium, an antimicrobial agent, at least one poloxamer, an organic solvent, and optionally a cellulose derivative which is at least partially soluble in organic solvents.
• the method comprises a single administration of the formulation, but more than one injection may be used according to the need and the length of the treatment.
• the method comprises multiple administrations of the formulation, as long as the number of administrations is lower than currently required for the specific biologically active agent.
• the administration may include a single injection, or multiple injections into multiple sites, if a large volume of the injection is required. Due to the advantages of the formulations of the present invention, it may not be necessary to use multiple injection sites, as the poorly-soluble drug is present in sufficient amount in relatively small volumes of the injection.
• the administration is usually an intramuscular injection.
• the administration may also be a subcutaneous administration, intraperitoneal administration, intradermal administration, or specific administration sites, such as intravulval administration for cows and sheep, intracaudal or ear administration for beef cattle, intramammary, and the like.
• the veterinary infections that may be treated according to the invention include the infections caused by the pathogens of swine, infections of cattle, infections of poultry, infections of companion animals, or infections of zoo- and wildlife animals.
• the organic solvent as described above is selected from the group consisting of N-methyl pyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol.
• NMP N-methyl pyrrolidone
• the organic solvent is NMP.
• the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237, poloxamer 338, and combination thereof.
• the poloxamer as described above is poloxamer 407.
• the cellulose derivative is hydroxypropyl cellulose.
• the antimicrobial agent is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tylvalosin, doxycycline, oxytetracycline.
• the antimicrobial agent is florfenicol.
• Florfenicol and N-methylpyrrolidone (NMP) were purchased from Sigma- Aldrich, Israel. Poloxamers, 407, 188, 338 and 237 were obtained from local representative of BASF. Amoxicillin, tylosin, Klucel® polymers (hydroxypropyl cellulose), PEG400, and propylene glycol were obtained as a gift from pharma companies. Water was purified on a column and distilled before use. Sodium chloride was purchased from Merck, Israel.
• florfenicol injectable formulations were prepared as follows:
• a weighed amount of florfenicol was placed in a mortar, and geometrically levigated, i.e. mixed in a mortar with comparable aliquots of the solution, until all of the weighed aliquot of prepared solution was used up.
• the gelation was measured by inverting a glass tube containing 0.5-1 mL of the formulation, at increasing temperatures. The temperature whereat the formulation stopped flowing down upon inversion was considered a primary gelation point. Alternatively, for preliminary screening, the temperature was elevated to 40°C and the time it took the formulation to become a gel-form was recorded.
• Florfenicol was determined using HPLC, using HP 1090 apparatus, with UV detector measuring absorbance at 224 nm. A C-18 250x4.6 5pm column was used, with elution at 1.2 ml/min, with 25:75 ACN:DDW mobile phase. Florfenicol eluted under these conditions at 4. -4.5 minutes.
• a syringe barrels of 5-mL syringes were cut into 2-mL segments to serve as holders - in a shape of a tube.
• One side was closed with Parafilm® sheet, and about 2-mL aliquots of the formulation at room temperature were accurately weighed into said prepared tube- holders, through 19G needle using a suitable syringe, thus evaluating the injectability of the formulation.
• the top side was then closed with another Parafilm® sheet and placed into a pre-heated oven to 40°C, for at least 15 minutes to ensure gelation.
• the Parafilm® sheets were then accurately removed, the tube-holder was placed into a sinker basket and immediately transferred into Caleva 6ST dissolution tester (USP Apparatus 2), set to 20 rpm at 40°C. The temperature was chosen to fit and mimic the body temperature of the target animal (swine).
• the dissolution medium was phosphate buffer USP, at pH 6.8, and a 900 mL volume was used per tube-holder. Samples were drawn from the dissolution medium at predetermined times, and the volume was corrected with fresh dissolution medium. At the end of the test, the tube-holders were washed in the dissolution vessels and vigorously mixed to obtain the recovery amount of the material to serve as the 100% reference. The percentile of maximal concentration of florfenicol at each time point with the standard deviation was reported.
• Example 1 comparative example
• Example 7 (30% florfenicol) of said publication was reproduced and tested under the described conditions.
• the publication contains little guidance as to the grade of hypromellose used, two grades having an apparent viscosity of below 20 cP at the tested low concentrations (HPMC K4M and HPMC K15M) were tested separately. Briefly, the poloxamers were accurately weighed, cooled and dissolved in a large portion of cold water at 4°C, followed by the addition of hydroxypropyl methyl cellulose (HPMC). The rest of the excipients were provided from stock solutions, and the remainder water content was added and thoroughly mixed.
• Formulation samples having total quantities of 25 grams were prepared, samples prepared utilizing HPMC K4M are referred to as sample preparation 1.1 and samples prepared utilizing HPMC K15M are referred to as sample preparation 1.2.
• Preparation 2.1 is according to an embodiment of the present invention and comprises both the cellulose based material hydroxypropyl cellulose; preparation 2.2 shows the effect of omission of the co-solvent; preparation 2.3 shows the effect of omission of hydroxypropyl cellulose (Klucel® EF) and the co-solvent NMP; and preparation 2.4 is a comparative preparation according to WO2012131678, having no co-solvent and no cellulose additive.
• Preparations 2.5 (of an embodiment of the invention) demonstrates a lower loading (20 wt% florfenicol) and 2.6 contain 20 % of florfenicol and no NMP for comparison with preparations 2.6.
• formulations having 20% loading according to the invention produce comparable yet somewhat more attenuated release of florfenicol with yet lower variability than the hypothetical 20% formulation of CN’802 with hypromellose instead of hydroxypropyl cellulose (preparation 1.5).
• the diamonds ( ⁇ ) represent preparation 3.1 (designated as“5 wt%”), solid squares ( ⁇ ) preparation 2.1 (designated as“10 wt%”), and solid triangles (A) preparation 3.2 (designated as“20 wt%”), with“%FFC” indicating the cumulative release percentile of florfenicol, and“t (h)” indicated time elapsed from the beginning of the experiment, in hours.
• gels according to the preparation 2.1 were produced, and NMP was substituted with either DMSO (preparation 4.1), propylene glycol (preparation 4.2), PEG 400 (preparation 4.3), or ethanol (preparation 4.4).
• Preparation 6.1 contained about 33 wt% of florfenicol, 6.2 about 36 wt%, and 6.3 about 39 wt%.
• compositions were syringeable via the 16G needle, injectable thereafter, and showed reverse thermal behavior, e.g. gelled at heating and liquefied again upon cooling.
• release profiles and rheology data are summarized in the Table 6 below.
• Nuflor® Merck Animal Health - florfenicol 30% solution in NMP
• a preparation (designated herein as 8.1) comprising 40 wt% of florfenicol, 12 wt% of poloxamer 407, 0.5 wt% of Klucel EF, 5 wt% of NMP and 42.5 wt% of water, with the gelation point of 21.7 °C, was administered at 40 mg/kg.
• the release profile of the preparation 8.1 at the same conditions as in the Example 7 is demonstrated in the table 9 below.
• FIG. 4 The plot of blood plasma concentrations of florfenicol versus time is demonstrated in Figure 4.
• the diamonds ( ⁇ ) represent Nuflor, solid squares ( ⁇ ) preparation 8.1, solid triangles (A) preparation 6.6, and X-signs (x) preparation 6.7, and the asterisks (*) preparation 6.8, with "C (ng/mL)” indicating the blood plasma concentration of florfenicol, and“t (h)” indicated time elapsed from the beginning of the experiment, in hours.
• compositions according to the invention comprising 30 wt% of amoxicillin were prepared.
• Preparation 9.1 contained both the co-solvent and the cellulose derivative at least partially soluble in organic solvents (hydroxypropyl cellulose), preparation 9.2 only hydroxypropyl cellulose, and 9.3 none of the additional excipients.
• the formulations were prepared along the lines as described for florfenicol.
• compositions were syringeable via the 16G needle, injectable thereafter, and showed reverse thermal behavior, e.g. gelled at heating and liquefied again upon cooling.
• release profiles data are summarized in the Table 11 below.
• compositions according to the invention comprising 15 wt% of tylosin were prepared.
• Preparation 10.1 contained both the co-solvent and the cellulose derivative at least partially soluble in organic solvents (hydroxypropyl cellulose), preparation 10.2 only hydroxypropyl cellulose, and 10.3 none of the additional excipients.
• the formulations were prepared along the lines as described for florfenicol.
• compositions were syringeable via the 16G needle, injectable thereafter, and showed reverse thermal behavior, e.g. gelled at heating and liquefied again upon cooling.
• release profiles data are summarized in the Table 12 below.

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